Injury-induced nociceptive sensitization in adult D. melanogaster

成年黑腹果蝇损伤引起的伤害性敏化

• 批准号: 10586054
• 负责人: GEOFFREY GANTER
• 金额: $ 7.1万
• 依托单位: UNIVERSITY OF NEW ENGLAND
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2023-07-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10586054
• 关键词: Abdomen; Address; Adult; Affect; Age; Aging; Analgesics; Anesthesia procedures; Animals; Behavioral; Biochemical; Biological Assay; Biological Metamorphosis; Biological Models; Bone Morphogenetic Proteins; Candidate Disease Gene; Chronic; Dose; Drosophila genus; Emotional; Epidemic; Exhibits; Exposure to; Future; Genes; Genetic; Genetic Models; Genome; Goals; Health Promotion; Human; Hypersensitivity; Injury; Intractable Pain; Investigation; Knowledge; Larva; Lasers; Lateral; Life; Longevity; Mammals; Maps; Measures; Mechanics; Mediating; Methods; Modeling; Molecular; Morphology; Neurons; Nociception; Nociceptors; Opiate Addiction; Opioid; Orthologous Gene; Pain; Pain Research; Pain management; Pathway interactions; Pharmaceutical Preparations; Population; Process; Protocols documentation; Quality of life; Reaction; Recovery; Resolution; Response Latencies; Rodent; Role; Severities; Sex Differences; Signal Transduction; Signaling Protein; Stimulus; System; Testing; Time; Tissues; Translating; Translations; UV injury; Ultraviolet Rays; Vacuum; addiction liability; age effect; allodynia; avoidance behavior; chronic pain; chronic pain management; economic impact; experimental study; fly; gene conservation; gene discovery; healing; health warning; human disease; injured; innovation; mature animal; neurophysiology; new therapeutic target; novel; pain model; pain reduction; peripheral pain; power analysis; response; restraint; sex; side effect; young adult

Project Summary Normal pain promotes health by warning us of potential tissue damage, but abnormal pain reduces the quality of life for millions around the world. Pain sensitization after injury also promotes health by reducing re-injury during healing. Some types of abnormal pain, including chronic pain, result from dysregulation of the pain sensitization system. Available treatment for chronic pain is inadequate, in part because the deleterious side effects of our best analgesics, the opioids, are made more hazardous by longer use. Better treatments for abnormal pain are badly needed. We propose to reveal novel targets for pain medications by exploiting the powerful genetic toolkit of the Drosophila model. When the fruit fly is injured by a controlled dose of ultraviolet (UV) radiation, the animal exhibits allodynia, a manifestation of nociceptive sensitization. This means that the injured animal will react with a nocifensive avoidance behavior in the form of an avoidance 'jump', in response to a thermal stimulus with a reduced delay, compared with uninjured animals. This injury induced sensitization paradigm has previously been used in larval flies to demonstrate that the nociceptor neuron requires signaling by the Bone Morphogenetic Proteins (BMP) pathway to produce allodynia. BMP signaling components in the fly are very similar to their mammalian orthologs. However, studies on larval flies are limited to the short time available before the larva pupariates, becoming insensitive while metamorphosis reorganizes the larval tissues to produce an adult. This project seeks to establish similar methods that can be applied to adult flies, which live for 35 or more days, a much longer time window for studying processes like chronic pain. Preliminary results indicate that UV-injured adults, like larvae, do indeed become hypersensitive to noxious stimuli. We are now ready to map out the time required for injured adults to become sensitized and then return to normal sensitivity, so that we can test the roles of genes that my serve to prolong pain sensitization, while others may shorten the hypersensitive period. The roles of sex and aging in pain sensitization will also be examined. Because of the high degree of functional conservation between fly and mammalian genes, components identified by these experiments may represent targets for novel medications for the treatment of abnormal pain in humans.

项目摘要 正常的疼痛通过警告我们潜在的组织损伤来促进健康，但不正常的疼痛会降低质量。 为全世界数以百万计的人提供生命的源泉。受伤后的疼痛敏感性也通过减少再次受伤来促进健康 在愈合过程中。某些类型的异常疼痛，包括慢性疼痛，是由疼痛调节失调引起的。 敏化系统现有的治疗慢性疼痛是不够的，部分原因是有害的一面， 我们最好的止痛药-阿片类药物-的作用因长期使用而变得更加危险。更好的治疗 异常疼痛是非常需要的。我们建议通过利用这些药物来揭示止痛药的新靶点。 果蝇模型的强大遗传工具包。当果蝇受到控制剂量的紫外线伤害时 (UV)在辐射的情况下，动物表现出异常性疼痛，这是伤害性敏化的表现。这意味着 受伤的动物会以回避“跳跃”的形式做出伤害性回避行为的反应， 与未受伤的动物相比，热刺激的延迟减少。这种损伤诱发了致敏作用 先前已经在果蝇幼虫中使用了一个范例来证明伤害感受器神经元需要信号传导 通过骨形态发生蛋白（BMP）途径产生异常性疼痛。骨形态发生蛋白信号成分 果蝇与它们的哺乳动物直系同源物非常相似。然而，对幼虫的研究仅限于短时间内， 在幼虫化蛹前可用，在变态重组幼虫组织时变得不敏感 才能生出一个成年人该项目旨在建立类似的方法，可以应用于成年苍蝇， 存活35天或更长时间，这对于研究慢性疼痛等过程来说是一个更长的时间窗口。初步 结果表明，紫外线损伤的成虫，像幼虫一样，确实对有害刺激变得过敏。我们 现在准备绘制出受伤的成年人变得敏感然后恢复正常所需的时间 敏感性，这样我们就可以测试基因的作用，这些基因可以延长疼痛敏感性，而其他基因可能 缩短过敏期。还将研究性别和年龄在疼痛致敏中的作用。 由于果蝇和哺乳动物基因之间高度的功能保守性， 这些实验所确定的可能代表治疗异常疼痛的新型药物的靶点 在人类身上。